CURRENT OASIS-7: Benefit to Doubling Clopidogrel Dose in ACS Patients Undergoing PCI

August 30, 2009

August 30, 2009 (Updated August 31) (Barcelona, Spain) — Doubling the loading and maintenance doses of clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) in ACS patients undergoing planned PCI significantly reduces stent thrombosis and cardiovascular events, largely driven by reductions in MI, without a significant increase in major bleeding.

In the overall cohort, which included 7855 patients who did not undergo PCI because no significant CAD was identified on the coronary angiogram or who discontinued therapy because they were scheduled for CABG surgery, there was no significant difference in the primary composite end point of death, MI, or stroke in patients randomized to the standard or doubled clopidogrel doses.

These are the results of the Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events/Optimal Antiplatelet Strategy for Interventions (CURRENT OASIS-7) presented here today at the European Society of Cardiology (ESC) 2009 Congress by lead investigator Dr Shamir Mehta (McMaster University, Hamilton, ON). In addition, researchers also showed there was no difference in the safety or efficacy of higher-dose aspirin when compared with lower-dose aspirin.

"Virtually every interventional cardiologist [in the world] is using clopidogrel today," Mehta told the media during a morning press conference. "Tomorrow, after the results of this trial are presented, based on these data, doctors are going to have to decide what to do. It's a simple therapy to institute, it's going from one pill to two pills per day, and the cost implications are virtually negligible and the benefits are large. So this maneuver could improve patient outcomes in PCI, and it's a fairly simple thing to institute rapidly."

Commenting on the results of the study for heartwire , Dr Douglas Weaver (Henry Ford Health System, Detroit, MI), who was not part of the CURRENT trial, agreed with Mehta, saying that doubling the dose of clopidogrel is an easy option for clinicians before other drugs, including the investigational oral antiplatelet agent ticagrelor (AstraZeneca) and the newly approved prasugrel (Effient, Lilly/Daiichi Sankyo), are available or in more widespread use.

"One week of therapy is not going to be associated with increased side effects, and it is a simple solution that interventionalists will probably use," said Weaver.

Dr Sanjay Kaul (Cedars Sinai Medical Center, Los Angeles, CA), however, who was not involved in the study but provided a comment to heartwire , said that as the trial failed to meet its primary end point, the analysis is compromised by a "false-positive" error rate. When this happens, Kaul said, conventional wisdom is to take the overall result as the most reliable treatment effect, and the absolute effect, in this case, is rather modest.

No Increased Bleeding Risk With High-Dose Aspirin

The CURRENT OASIS-7 study is a 2x2 factorial, randomized trial studying the optimal dose of clopidogrel and aspirin in ACS patients presenting to an emergency department and scheduled to undergo an early invasive strategy with intent to perform PCI no later than 72 hours after randomization. Mehta said that recent data have suggested that doubling the loading and maintenance dose of clopidogrel would result in a greater and more rapid antiplatelet effect, which would translate into better clinical outcomes. Regarding aspirin, there is large variance worldwide, including disparities in the clinical guidelines, about the optimal aspirin dose for the treatment of ACS.

In this trial, patients assigned to high-dose clopidogrel received a 600-mg loading dose on day 1 and then 150 mg once daily for next seven days, followed by 75 mg once daily until 30 days. Patients in the standard clopidogrel arm received a 300-mg loading dose on day 1, followed by 75 mg once daily until 30 days. Patients were also assigned in an open-label manner to 300 to 325 mg of aspirin once daily or 75 to 100 mg aspirin once daily.

Compared with low-dose aspirin, use of aspirin 300 to 325 mg did not result in any significant differences in major bleeding, defined as TIMI major bleeding or CURRENT major and severe bleeding. Mehta said that the CURRENT definitions of bleeding are more sensitive than TIMI and primarily consider other factors such as the need for inotropes, surgery, or a blood transfusion. In terms of efficacy, there was no significant difference in the primary outcome or its components, although there was a numerical reduction with the higher dose of aspirin.

Results of the Aspirin Dose Comparison: Efficacy and Bleeding

Measure Aspirin 75–100 mg Aspirin 300–325 mg Hazard ratio (95% CI)
Cardiovascular death, MI, and stroke (n=25 087) 4.4 4.2 0.96 (0.85–1.08)
PCI cohort (n=17 232) 4.2 4.1 0.98 (0.84–1.13)
No PCI cohort (n=7855) 4.7 4.4 0.92 (0.75–1.14)
Stent thrombosis 2.1 1.9 0.91 (0.73–1.12)
TIMI major bleed 1.03 0.97 0.94 (0.73–1.21)
CURRENT major bleed 2.3 2.3 0.99 (0.84–1.17)
CURRENT severe bleed 1.7 1.7 1.00 (0.83–1.21)

"The rationale that we have used in the past for low-dose aspirin has been that if we use high-dose aspirin there will be more bleeding," said Mehta. "Certainly the observational data in the past have suggested that, but we've now done a randomized trial showing that there is no increased bleeding with higher doses of aspirin. In fact, if you look at the data carefully in this study, the higher-dose aspirin group consistently did better, both for the primary outcome and for the PCI group. So there is really no reason not to use high-dose aspirin, at least for 30 days after placing a stent."

Although not practice changing in the US, where physicians have been more likely to use high-dose aspirin in the past, Mehta said the results are likely to have an impact on Canadian and European physicians, who typically use the lower dose of aspirin.

Doubling the Dose of Clopidogrel

In the clopidogrel arm of the study, researchers observed no significant difference in the overall cohort of patients who received the higher loading and maintenance doses, most likely because the patients who did not undergo PCI had no significant coronary disease by angiogram or the drug was stopped when patients were scheduled for CABG surgery, said Mehta. In focusing on the 17 232 patients who underwent PCI, there was a significant 15% reduction in cardiovascular, death, MI, and stroke, and this reduction was driven by a significant 22% reduction in the risk of MI. In addition, there was a significant 42% reduction in the risk of definite stent thrombosis.

Double vs Standard Dose of Clopidogrel: Primary Outcome and Components

Measure Standard clopidogrel therapy Double clopidogrel therapy Hazard ratio (95% CI)
Cardiovascular death, MI, and stroke, overall cohort (n=25 087) 4.4 4.2 0.95 (0.84–1.07)
PCI cohort (n=17 232) 4.5 3.9 0.85 (0.74–0.99)
No PCI cohort (n=7855) 4.2 4.9 1.17 (0.95–1.44)
MI, overall cohort 2.2 1.9 0.86 (0.73–1.03)
PCI cohort 2.6 2.0 0.78 (0.64–0.95)
No PCI cohort 1.4 1.7 1.25 (0.87–1.79)
Cardiovascular death, overall cohort 2.2 2.1 0.96 (0.81–1.14)
PCI cohort 1.9 1.9 0.96 (0.77–1.19)
No PCI cohort 2.8 2.7 0.96 (0.74–1.26)
Stroke, overall cohort 0.5 0.5 0.99 (0.70–1.39)
PCI cohort 0.4 0.4 0.88 (0.55–1.41)
No PCI cohort 0.8 0.9 1.11 (0.68–1.82)

In terms of the bleeding risks, there was no difference with the standard and doubled clopidogrel doses when the TIMI major bleeding definition was used. However, there was a significant increase in bleeding when the CURRENT major and severe bleeding definition was used, and this was driven by an increased need for red blood cell transfusions. Importantly, said Mehta, there was no difference in fatal bleeding, intracranial hemorrhage (ICH), or CABG-related major bleeding.

Bleeding Outcome and Stent Thrombosis in PCI Population

Outcome Standard clopidogrel therapy (n=8684) Double clopidogrel therapy (n=8548) Hazard ratio (95% CI)
Definite stent thrombosis 1.2 0.7 0.58 (0.42–0.79)
TIMI major bleeding 0.5 0.5 1.06 (0.70–1.61)
CURRENT major bleeding 1.1 1.6 1.44 (1.11–1.86)
CURRENT severe bleeding 0.8 1.1 1.39 (1.02–1.90)
Fatal bleeding 0.15 0.07 0.47 (0.18–1.23)
ICH 0.035 0.046 1.35 (0.30–6.04)
Red blood cell transfusion >2U 0.91 1.35 1.49 (1.11–1.98)
CABG-related major bleeding 0.1 0.1 1.69 (0.61–4.7)

During the press conference, Mehta said the clinical implications of this study are such that for every 1000 patients with ACS receiving PCI, doubling the loading and maintenance dose of clopidogrel will prevent an additional six MIs and seven stent thromboses with an excess three severe bleeds and no increase in fatal, CABG-related, or TIMI major bleeds. For those not undergoing PCI, they should continue using the standard dose of clopidogrel, he said.

"You reduce stent thrombosis, and you reduce MI. It's not something that has to pass through any regulatory channels," Mehta told heartwire . "When an angioplasty is done tomorrow morning, you can send the patient home with two tablets and they're going to get a benefit."

During the late-breaking clinical-trials session, discussant Dr Frans Van de Werf (University of Leuven, Belgium) agreed with the conclusions of the CURRENT investigators, stating that most ACS patients undergoing PCI should receive the doubled clopidogrel dose because of the favorable net clinical benefit.

"In other words, the price to pay in terms of bleeding complications is small and certainly acceptable," he said, adding that ACS patients treated medically should continue to receive the standard clopidogrel dose. He contradicted the conclusions reached by the investigators, however, regarding aspirin, saying the data provide no support for the use of the higher dose.

Kaul, on the other hand, said the requirement for red cell transfusion is a clinically relevant criterion for bleeding. In his opinion, "it is not unreasonable to conclude that the benefit of double-dose clopidogrel does not outweigh its risk" and that one could argue that the results do not provide support for doubling the dose of clopidogrel.

Van de Werf, speaking about aspirin, contradicted the conclusions reached by the investigators, saying the data provide no support for the use of the higher dose.

Van de Werf also noted the borderline significant interaction between aspirin and clopidogrel doses. However, he agreed with the investigators, who suggested the interaction might be a "spurious finding" since it was attenuated to nonsignificance when MI and stent thrombosis were used as an outcome measure. He also noted the "interesting finding" that patients treated with proton-pump inhibitors and those who were not received similar benefits with the doubled clopidogrel dose. Future research is still needed to test the effectiveness of doubling the dose in patients with the known loss-of-function polymorphism associated with clopidogrel resistance, as well studies with higher-dose clopidogrel compared with newer agents, among them prasugrel and ticagrelor.

Sanofi-Aventis and Bristol-Myers Squibb sponsored the CURRENT OASIS-7 study.